- Activating Autophagy Enhanced the Antitumor Effect of Antibody Drug Conjugates Rituximab-Monomethyl Auristatin E. [Journal Article]
- FIFront Immunol 2018; 9:1799
- CONCLUSIONS: Our data elucidated the critical relationship between autophagy and apoptosis in Rituximab-MMAE-based therapy and highlighted the potential approach for NHL therapy by combined administration of the ADC and autophagy activator.
- Sinomenine inhibits the growth of melanoma by enhancement of autophagy via PI3K/AKT/mTOR inhibition. [Journal Article]
- DDDrug Des Devel Ther 2018; 12:2413-2421
- CONCLUSIONS: Our study has identified a novel function of SIN and provided a molecular basis for potential applications of SIN in the treatment of melanoma and other cancers.
- Study of the antimalarial activity of 4-aminoquinoline compounds against chloroquine-sensitive and chloroquine-resistant parasite strains. [Journal Article]
- JMJ Mol Model 2018 Aug 17; 24(9):237
- This study is concerned with identifying features of 4-aminoquinoline scaffolds that can help pinpoint characteristics that enhance activity against chloroquine-resistant parasites. Statistically val...
This study is concerned with identifying features of 4-aminoquinoline scaffolds that can help pinpoint characteristics that enhance activity against chloroquine-resistant parasites. Statistically valid predictive models are reported for a series of 4-aminoquinoline analogues that are active against chloroquine-sensitive (NF54) and chloroquine-resistant (K1) strains of Plasmodium falciparum. Quantitative structure activity relationship techniques, based on statistical and machine learning methods such as multiple linear regression and partial least squares, were used with a novel pruning method for the selection of descriptors to develop robust models for both strains. Inspection of the dominant descriptors supports the hypothesis that chemical features that enable accumulation in the food vacuole of the parasite are key determinants of activity against both strains. The hydrophilic properties of the compounds were found to be crucial in predicting activity against the chloroquine-sensitive NF54 parasite strain, but not in the case of the chloroquine-resistant K1 strain, in line with previous studies. Additionally, the models suggest that 'softer' compounds tend to have improved activity for both strains than do 'harder' ones. The internally and externally validated models reported here should also prove useful in the future screening of potential antimalarial compounds for targeting chloroquine-resistant strains. Graphical Abstract Predictive models reveal linear relationships for activity of 4-aminoquinoline analogues active against chloroquine-sensitive strains of Plasmodium falciparum.
- USP9X inhibition improves gemcitabine sensitivity in pancreatic cancer by inhibiting autophagy. [Journal Article]
- CLCancer Lett 2018 Aug 14
- Gemcitabine is the cornerstone of pancreatic cancer treatment. Although effective in most patients, development of tumor resistance to gemcitabine can critically limit its efficacy. The mechanisms re...
Gemcitabine is the cornerstone of pancreatic cancer treatment. Although effective in most patients, development of tumor resistance to gemcitabine can critically limit its efficacy. The mechanisms responsible for this phenomenon remain elusive, but evidence suggests that ubiquitin-specific peptidases (USPs) may be key regulators in cancer chemo-resistance. The present study aimed to investigate the role of USP9X in gemcitabine resistance using in vitro pancreatic cell lines and a mouse xenograft model. We found that the expression of USP9X in pancreatic cancer cells was positively correlated with gemcitabine resistance, and that inhibition of USP9X by WP1130 sensitized pancreatic cancer cells to gemcitabine. Gemcitabine induced autophagy, and blocking autophagy with chloroquine improved sensitivity to gemcitabine. We also found that WP1130 inhibited gemcitabine-induced autophagy, and blocking autophagy abolished the sensitization effect of WP1130 on gemcitabine in pancreatic cancer cells. Finally, combined gemcitabine and WP1130 treatment enhanced the anti-tumor effect of gemcitabine by suppressing autophagy in vivo. Taken together, these results demonstrate that inhibition of USP9X sensitized pancreatic cancer cells to gemcitabine by inhibiting autophagy, which provides a novel insight into gemcitabine resistance in pancreatic cancer.
- Emerging Southeast Asian PfCRT mutations confer Plasmodium falciparum resistance to the first-line antimalarial piperaquine. [Journal Article]
- NCNat Commun 2018 Aug 17; 9(1):3314
- The widely used antimalarial combination therapy dihydroartemisinin + piperaquine (DHA + PPQ) has failed in Cambodia. Here, we perform a genomic analysis that reveals a rapid increase in the prevalen...
The widely used antimalarial combination therapy dihydroartemisinin + piperaquine (DHA + PPQ) has failed in Cambodia. Here, we perform a genomic analysis that reveals a rapid increase in the prevalence of novel mutations in the Plasmodium falciparum chloroquine resistance transporter PfCRT following DHA + PPQ implementation. These mutations occur in parasites harboring the K13 C580Y artemisinin resistance marker. By introducing PfCRT mutations into sensitive Dd2 parasites or removing them from resistant Cambodian isolates, we show that the H97Y, F145I, M343L, or G353V mutations each confer resistance to PPQ, albeit with fitness costs for all but M343L. These mutations sensitize Dd2 parasites to chloroquine, amodiaquine, and quinine. In Dd2 parasites, multicopy plasmepsin 2, a candidate molecular marker, is not necessary for PPQ resistance. Distended digestive vacuoles were observed in pfcrt-edited Dd2 parasites but not in Cambodian isolates. Our findings provide compelling evidence that emerging mutations in PfCRT can serve as a molecular marker and mediator of PPQ resistance.
- Chloroquine plays a cell-dependent role in the response to treatment of pancreatic adenocarcinoma. [Journal Article]
- OOncotarget 2018 Jul 20; 9(56):30837-30846
- In this study, our aim is to assess the role played by autophagy and its inhibition in the different PDAC cellular compartments, and its involvement in chemo-resistance using primary human pancreatic...
In this study, our aim is to assess the role played by autophagy and its inhibition in the different PDAC cellular compartments, and its involvement in chemo-resistance using primary human pancreatic cancer-derived cells (PCC) and Cancer Associated Fibroblasts (CAF). Autophagy flux, as measured by LC3-I and -II in the presence of Chloroquine, showed a variable level in PCC and CAFs. We found no correlation between autophagy level and degree of tumor differentiation. Association of Chloroquine with gemcitabine, 5FU, oxaliplatin, irinotecan and docetaxel revealed that its effect on survival is cell- and drug-dependent in vitro and in vivo. In addition, we demonstrated that autophagy in CAFs can play an important role in sensitizing PDAC to anticancer treatments since its inhibition increased the resistance of PCCs to gemcitabine. In conclusion, this work clearly shows a heterogeneity in the effect of Chloroquine and highlights a role of CAFs autophagy in sensitizing tumors to treatments. It also reveals that the role of autophagy is more complex than expected in PDAC as well as its sensitivity to treatments.
- Isolation, characterization, and biological evaluation of a potent anti-malarial drimane sesquiterpene from Warburgia salutaris stem bark. [Journal Article]
- MJMalar J 2018 Aug 15; 17(1):296
- CONCLUSIONS: This study proves that Warburgia salutaris contains components (including iso-mukaadial acetate) that exhibit anti-malarial activity and scientifically validates the use of this plant in folk medicine.
- The behavioral study on the interactive aggravation between pruritus and depression. [Journal Article]
- BBBrain Behav 2018; 8(6):e00964
- CONCLUSIONS: This study established an appropriate cross aggravation experimental mode and demonstrated that there is cross aggravation between pruritus and depression. The illumination of related mechanisms underlying this cross aggravation effect will provide theoretical basis for the prevention and treatment of depression and pruritus.
- Immune thrombocytopenia induces autophagy and suppresses apoptosis in megakaryocytes. [Journal Article]
- MMMol Med Rep 2018 Aug 09
- Immune thrombocytopenia (ITP) is the main pathogenesis of excessive platelet destruction and abnormal megakaryocyte apoptosis, however, the mechanism underlying this abnormality in megakaryocytes rem...
Immune thrombocytopenia (ITP) is the main pathogenesis of excessive platelet destruction and abnormal megakaryocyte apoptosis, however, the mechanism underlying this abnormality in megakaryocytes remains to be elucidated. Since autophagy and apoptosis are closely interrelated, it can be speculated that the abnormal apoptosis of ITP megakaryocytes is associated with autophagy. To test this hypothesis, a total of 14 patients with ITP and 23 healthy controls were recruited. MEG‑01 cell line was cultured in vitro, and morphological changes were observed by light microscopy, apoptosis was evaluated by flow cytometric analysis of Annexin V‑FITC/propidium iodide staining and western blot analysis of B‑cell lymphoma (Bcl)‑2, Bcl‑associated X protein (Bax), Beclin‑1 and cleaved caspase 3. Apoptotic abnormalities and autophagy were observed in the ITP plasma group. Furthermore, Bax expression was downregulated, while Beclin‑1 was upregulated. Chloroquine can block autophagy induced by ITP and remove the ITP plasma inhibition of apoptosis. Therefore, it may be concluded that ITP may induce autophagy, the inhibition of which may be a novel treatment for ITP.
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- A barcode of multilocus nuclear DNA identifies genetic relatedness in pre- and post-Artemether/Lumefantrine treated Plasmodium falciparum in Nigeria. [Journal Article]
- BIBMC Infect Dis 2018 Aug 13; 18(1):392
- CONCLUSIONS: Persistence of DNA-detectable parasitaemia in more than 18% of cases after treatment and indications of genetic relatedness between pre- and post-treatment infections warrants further investigation of a larger population for signs of reduced ACT efficacy in Nigeria.